title: Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.
abstract: BACKGROUND
  IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy.
  
  
  OBJECTIVE
  To investigate the association between filaggrin loss-of-function mutations and peanut allergy.
  
  
  METHODS
  Case-control study of 71 English, Dutch, and Irish oral food challenge-positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥ 8 mm and/or peanut-specific IgE ≥ 15 kUL(-1)) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis.
  
  
  RESULTS
  Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge-positive patients (P = 3.0 × 10(-6); odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10(-5); odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis.
  
  
  CONCLUSIONS
  Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.
authors.affiliation: Epithelial Genetics Group, Division of Molecular Medicine, University of Dundee, Dundee, United Kingdom. s.j.brown@dundee.ac.uk
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Brown
authors.forename: Yuka
authors.initials: Y
authors.lastname: Asai
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.forename: Linda E
authors.initials: LE
authors.lastname: Campbell
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Haihui
authors.initials: H
authors.lastname: Liao
authors.forename: Kate
authors.initials: K
authors.lastname: Northstone
authors.forename: John
authors.initials: J
authors.lastname: Henderson
authors.forename: Reza
authors.initials: R
authors.lastname: Alizadehfar
authors.forename: Moshe
authors.initials: M
authors.lastname: Ben-Shoshan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.forename: Graham
authors.initials: G
authors.lastname: Roberts
authors.forename: Laury J N
authors.initials: LJ
authors.lastname: Masthoff
authors.forename: Suzanne G M A
authors.initials: SG
authors.lastname: Pasmans
authors.forename: Peter C
authors.initials: PC
authors.lastname: van den Akker
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Jonathan O'B
authors.initials: JO
authors.lastname: Hourihane
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Gideon
authors.initials: G
authors.lastname: Lack
authors.forename: Ann
authors.initials: A
authors.lastname: Clarke
authors.forename: Peter R
authors.initials: PR
authors.lastname: Hull
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
mesh_terms: D002170:Canada; D016022:Case-Control Studies; D005060:Europe; D000091344:Filaggrin Proteins; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D006969:Hypersensitivity, Immediate; D007381:Intermediate Filament Proteins / Q000235:genetics*; D007494:Ireland; D009426:Netherlands; D021183:Peanut Hypersensitivity / Q000235:genetics*; D012307:Risk Factors
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins